PROJECT SUMMARY As the prevalence of age-related cognitive decline and Alzheimer?s disease continue to grow, understanding the mechanistic causes of these is becoming increasingly important. Recent clinical studies have linked increased stiffness of the large arteries to both impaired memory and Alzheimer?s disease. It is hypothesized that these relations are a result of large artery stiffness-induced cerebrovascular dysfunction. Increased large artery stiffness leads to greater pulsatility of pressure and blood flow in the cerebral vasculature, which is known to cause vascular damage. Dysfunction of both cerebral resistance arteries and cerebral microvessels are associated with cognitive impairment and greater Alzheimer?s disease-related neuropathology. Furthermore, amyloid-? (A?) induces cerebrovascular damage, and cerebrovascular impairment can increase A? accumulation, thus creating a vicious cycle of cerebrovascular dysfunction and neuropathology. The goal of the proposed studies is provide the first proof-of-concept evidence that age-related increases in large artery stiffness lead to cognitive decline and neuropathology associated with impaired cerebrovascular function. To do so, we will employ a transgenic mouse model of greater large artery stiffness, as well as a pharmacological intervention to prevent age-related increases in large artery stiffness. These models will be evaluated alone and in combination with a model of greater A? production. In Aim 1, we will assess the effects of large artery stiffness on cognitive function and Alzheimer?s disease-related neuropathology. In Aim 2, we will determine the effect of large artery stiffness on cerebral resistance artery function and cerebral blood flow. In addition, we will examine the role of oxidative stress in the cerebral resistance artery dysfunction induced by stiff large arteries and greater pressure pulsatility. In Aim 3, we will examine the effect of large artery stiffness on cerebral microvascular function. In addition, we will perform transcriptome analysis of microvascular endothelial cells as a means to identify candidates for the mechanisms involved. The knowledge to be gained by completing the proposed aims could identify novel therapeutic targets for the prevention or attenuation of age-related cognitive decline and Alzheimer?s disease.